Given the profound social and economic challenges of caring for the elderly population, strategies for promoting healthy aging are a central focus fo aging research. Exercise has been documented to protect against diseases of aging such as diabetes and cancer; exercise also promotes extended mobility and can enhance immune system function. Molecular understanding of how exercise benefits translate into healthy aging is thus of clear interest, but this issue has not been addressed extensively at the genetic level. We study fundamental processes relevant to healthy aging in the 959-celled nematode C. elegans. Recently we made a fascinating discovery- C. elegans can exercise to exhibit training benefits. Our initial studies suggest that AMPK, needed for mammalian exercise benefit, is also needed for C. elegans training, and that nematodes that exercise age more gracefully than those that do not exercise. Because it is critical to understand how tissue-specific and organism-wide health benefits are induced by exercise, and exhaustive genetics have not been applied to this problem, we propose to develop a C. elegans exercise model. Aim 1 is to optimize an exercise training protocol for C. elegans. We will vary swim regimens to establish an optimal training protocol that generates the most robust difference between trained and untrained as evaluated by a state-of-the-art motion analysis program. Data will define a protocol that can be applied in genetic, molecular, pharmacological, and cell biological analyses of exercise benefits in the powerful C. elegans model. Aim 2 is to test whether muscle responses to training are conserved from nematodes to humans. We will ask whether training-induced mitochondrial biogenesis, specific transcriptional changes, and specific gene activities needed in human exercise training are required for C. elegans training benefits. This work will provide the first documentation of the molecular and cell biological changes that accompany exercise training in C. elegans and will constitute the first test of whether exercise mechanisms are conserved. Aim 3 is to show that exercise improves function of multiple organ systems that would otherwise decline in aging animals. We will also begin to address whether specific longevity pathways are activated to contribute to exercise benefits. Data will provide the first evidence of a positive impact of exercise on C. elegans aging, and might highlight specific aging biomarkers that are affected. Our studies may also implicate insulin signaling, EGF signaling, and/or dietary restriction longevity pathways in exercise benefits. Our proposed development of the C. elegans exercise model will establish a powerful new system for addressing fundamental exercise benefit mechanisms that might inspire molecular strategies for healthy human maintenance. PUBLIC HEALTH RELEVANCE: Exercise has a profound positive impact on health of the aging population, having been reported to protect against age-associated diseases including cancer, diabetes, and cardiovascular disease, and to maintain muscle, immune system, and nervous system function. Still, how exercise promotes healthy aging remains poorly understood at the genetic level. We propose to develop the first exercise model in the simple animal C. elegans, show that training benefits are mediated by mechanisms conserved between nematodes and humans, and begin to address how exercise promotes healthy aging. Because this model is uniquely suited for in vivo studies and genetic manipulation, pioneering work in C. elegans may provide unexpected insights that promote development of novel anti-aging interventions.